Allergy information for: Cherry (Prunus avium )

Like many other allergies to fresh fruits and vegetables, cherry allergy can take two different forms. In the North of Europe, a milder form of cherry allergy is associated to birch-pollen allergy due to the similarity between a protein in birch that causes birch-pollen allergy, and a cherry protein. This is called the birch-fruit syndrome with symptoms confined largely to the mouth, causing a condition called “oral allergy syndrome” (OAS). The molecule, known as an allergen, involved in this kind of allergy does not survive cooking. Therefore, people who react to this allergen can tolerate cooked cherry. Individuals with cherry allergy might develop adverse reactions to other fruits including apple, pear, apricot, nuts such as hazelnut, or vegetables such as celeriac (celery tuber) and carrot.

In Mediterranean countries, people with cherry allergy do not have birch-pollen allergy. Instead they often have allergy to peach. These individuals develop adverse reactions to cherry because of the similarity between the allergens in peach and cherry. Symptoms are more severe including generalised urticaria, abdominal pain, vomiting and life-threatening symptoms, sometimes in addition to the OAS. The allergen that causes this kind of allergy is tough and the allergenicity survives in processed foods such as jams and juices. As a result, individuals with this kind of allergy cannot eat even cooked fruit. They also tend to develop adverse reactions to other fruits including apple, peach, apricot, plum, and nuts such as hazelnut and walnut.

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Clinical History

Number of Studies:1-5

Number of Patients:>50

Symptoms:

Several studies have reported symptoms of cherry allergy. They include oral allergy syndrome (OAS) with mild itching of the lips, tongue or throat in patients with reported allergy to cherry and a positive IgE CAP to birch pollen (Scheurer et al. 2001).

Skin Prick Test

Purified allergens (recombinant (r) Pru av 1; rPru av 4; and lipid transfer protein: rPru av 3), commercial cherry extacts and home-made extracts as follows. Fresh fruits were cut and homogenised in acetone/dry ice at -60 to -65°C and the mixture was stored overnight and cooled with dry ice. The resulting precipitates were washed twice with acetone (–60°C) and once with chilled acetone-diethyl ether (1:1, –60°C). The filter residue was lyophilized. 2 gr of the obtained acetone powder was extracted with 30 mL of PBS (0.01M potassium phosphate and 0.15 M NaCl (pH 7.4)). The suspension was centrifuged for 45 minutes at 20,000g, and the supernatant was filtered through a fiber glass prefilter (Ballmer-Weber et al. 2002).

Protocol: (controls, definition of positive etc)

Pastorello et al. 1994 used histamine dihydrochloride (10 mg/mL) as a positive control, and the glycerol-containing diluent of the prick solution as a negative control. A wheal graded at least 2+was regarded as positive.

Ballmer-Weber et al. 2002 used histamine dihydrochloride (10 mg/mL) as a positive control, and the glycerol-containing diluent of the prick solution as a negative control. A wheal size of 7 mm2 or greater was regarded as positive.

Number of Patients:

21 patients (Pastorello et al. 1994)

79 subjects were included in the study: 24 Swiss patients (group 1) with a positive double-blind placebo-controlled food challenge result to cherries, 23 patients with birch pollen allergy but without cherry allergy (group 2), 23 nonatopic subjects (group 3), and 9 Spanish patients with a history of a cherry allergy (group 4) (Ballmer-Weber et al. 2002).

Summary of Results:

All patients of Pastorello et al. (1994) showed a positive SPT.

SPT responses with rPru av 1, rPru av 4, and rPru av 3 were positive in 92%, 17%, and 4% respectively of the patients in group 1; in 74%, 30%, and 0% respectively of the patients in group 2; in 0%, 22%, and 89% respectively of the patients in group 4; and negative for all nonatopic subjects (group 3). Thus the sensitivity of a positive SPT response to at least one of the 3 RAs was 96%. The specificities, negative predictive values, and positive predictive values with the 3 RAs were 100%, 96%, and 100% if calculated in relation to the nonatopic control group but 17%, 79%, and 60% when calculated in relation to the control group with birch pollen allergy (Ballmer-Weber et al. 2002)

IgE assay (by RAST, CAP etc)

Number of Studies:0

Food/Type of allergen:

Cherry extract and recombinant cherry Pru av 1. Fresh fruits were cut and homogenised in acetone/dry ice at -60 to -65°C ant the mixture was stored overnight and cooled with dry ice. The resulting precipitates were washed twice with acetone (–60°C) and once with chilled acetone-diethyl ether (1:1, –60°C). The filter residue was lyophilized. 2 gr of the obtained acetone powder was extracted with 30 mL of PBS (0.01M potassium phosphate and 0.15 M NaCl (pH 7.4)). The suspension was centrifuged for 45 minutes at 20,000g, and the supernatant was filtered through a fiber glass prefilter (Scheurer et al. 1997)

101 German patients with a clinical history of OAS to cherry and birch pollen and 7 Italian patients with reactions in open food challenges to cherry (Scheurer et al. 2001).

Summary of Results:

89 % of the patients had IgE to rPru a 1 with 18 sera from 19 individuals having IgE which reacted with cherry extract. For all the patients the maximal histamine release was at a concentration of 0.01 mg/ml (Scheurer et al. 1997).

Immunoblotting

Immunoblotting separation:

The extracts were separated in a discontinuous buffer system in an SDS-polyacrylamide gradient gel with a 6% stacking gel and a 7.5% to 20% separation gradient. Samples were boiled and reduced with beta-mercaptoethanol (Pastorello et al. 1994) [156]

Proteins were separated by means of SDS-PAGE by using a Bio-Rad Mini Protean cell. The 15% separating gel was overlaid with a 5% stacking gel. Recombinant Pru av 4 was reduced with 1,4-dithiothreitol and rPru av 1 and rPru av 3 were applied under nonreducing conditions (Ballmer-Weber, et al 2002).

The proteins were transferred onto 0.2 µm of nitrocellulose membranes by means of tank blotting. The nitrocellulose membrane was blocked and incubated with patient sera. IgE antibody detection was performed with alkaline phosphatase-conjugated mouse anti-human IgE (1:750) and blots were developed with the AP Conjugate Substrate Kit (Ballmer-Weber et al. 2002).

Immunoblotting results:

88% of sera (16 of 18) of Pastorello et al. 1994 [156], showed Ig E binding to a 13 kDa protein and 77% (14 of 18) to a 30 kDa protein . The other IgE -binding components were: 20 kDa (8 of 18, 44%), 70 kDa (7 of 18, 38%), 14 kDa (6 of 18, 33%), 48 kDa (5 of 18, 27%), 17 kDa (3 of 18, 16%), and 50 kDa (3 of 18, 16%). Of the seven patients with negative responses to birch pollen, five showed only one IgE-binding component at 13 kDa, and two (patients 5 and 6) also had a second band at 30 kDa.

IgE from all tested sera (6/6) reacted with a dominant band of 18-19 kDa in the cherry extract. Additional bands of lower intensity (15 kDa) were recognised by four sera and of higher molecular masses (34, 55, 65 kDa) by two sera (Scheurer et al. 1997).

All sera tested (5) displayed IgE binding to the 30 kDa component. Three patients also reacted to proteins at 67-90 kDa and one of them to a 17, 32 and 40 kda proteins (Inschlag et al. 1998)

92% of sera of Ballmer-Weber et al. 2002 showed IgE binding to cherry extract on immunoblots. All patients' sera positive to one of the recombinant allergens reacted with polypeptides in the molecular weight range between 9 kDa and approximately 18 kDa, corresponding to Pru av 1, Pru av 3, and Pru av 4. In addition, weakly IgE reactivite polypeptides were observed in the higher molecular weight range (>50 kDa), which probably represents proteins with cross-reactive carbohydrate determinants. No IgE reactivity was found against a putative 23-kd allergen, which has been described as a thaumatin-like protein.

Oral provocation

DBPCFCs were performed by means of a 2-step spit (local mucosal challenge) and swallow procedure. Two different drinks, identical in color, texture, and taste, were prepared contained 75 g of pitted cherries, 15 g of wheat flour, 10 g of cabbage, 6 teaspoons of mint syrup, 15 g of cocoa, a pinch of saffron, and 135 g of water mixed in a blender. The placebo drink contained the same ingredients but no cherries and, in addition, 13 g of sugar and 27 g of beetroot juice (Ballmer-Weber et al. 2002).

In patients with birch pollen allergy but without cherry allergy and nonatopic control subjects, an open challenge was performed. These patients had to chew and swallow 6 fresh cherries (Ballmer-Weber et al. 2002)

79 subjects were included in the study: 24 Swiss patients (group 1) with a positive double-blind placebo-controlled food challenge result to cherries, 23 patients with birch pollen allergy but without a history of cherry allergy (group 2), 23 nonatopic subjects (group 3), and 9 Spanish patients with a history of a cherry allergy (group 4) (Ballmer-Weber et al. 2002).

Dose response:

Patients chewed the fruit for 1 minute and then spit it out. If no symptoms appeared within 15 minutes, the challenge was repeated with increasing amounts from 250mg up to 64 g. Patients were asked not to spit out the last two doses but to swallow the fruit instead. 60 g of cherry fruit was required to elicit a reaction (Pastorello et al. 1994) [156]

In the DBPCFCs 16 patients complained about symptoms strictly localized to the oral cavity (oral allergy syndrome, OAS). In 7 patients, symptoms were not restricted to the oral cavity but also dyspnea, dysphagia, rhinitis, gastrointestinal symptoms. One patient was not challenged because she had a severe allergic reaction with urticaria, angioedema, severe dyspnea, cough, and gastrointestinal symptoms accompanied by severe pain after cherry consumption. Subjects with birch allergy and no history of cherry allergy (group 2) and non-atopic (group 3) did not experience any reaction during open provocation with fresh cherries (Ballmer-Weber et al. 2002).

Five overlapping recombinant Pru av 1 fragments representing the entire amino acid sequence corresponding to the 'P-loop' region, with lengths of approximately 60-120 residues have been investigated. Weak IgE binding capacity was measured exclusively with Pru av IF4 (residues 1-120) by immunoblotting, but none of the fragments showed allergenicity in the rat basophil leukaemia cell mediator release assay. Site-directed mutagenesis experiments with Pru av 1 revealed that amino acid S112 is critical for IgE binding of almost all patients sera tested. This residue appears to be essential residue for preserving the structure of a cross-reactive IgE epitope. (Scheurer et al 1999).

Mutagenesis of Glu45 and Ser112 of Pru av 1 to Pru av 1 Trp45, Ala112, Pro112 was performed by PCR and the IgE reactivity determined by EAST and immunoblotting. Disruption of the native tertiary structure of Pru av 1 upon the mutation of Pro112 leads to the nearly complete loss of the IgE reactivity indicating that the cross-reactive IgE-binding epitopes of Pru av 1 are predominantly conformational rather than sequential. The mutation of Glu45 to Trp45 in the P-loop region, significantly reduced IgE binding to Pru av 1 in a subgroup of cherry-allergic patients therefore, this residue is involved in a cross-reactive IgE epitope. The mutation Ala112 did not influence IgE binding to Pru av 1 (Neudecker et al. 2003)

Influence of thermal processing and nonenzymatic as well as enzymatic browning reactions on Pru av 1 was investigated by Gruber et al (2004). Thermal unfolding of the allergen occurred at a calculated mellting temperature of 66.3°C. Correct refolding occurred after cooling. Allergenicity of Pru av 1 was reduced by enzymatic polyphenol oxidation and Maillard reaction induced by carbohydrate breakdown products.

Nature of main cross-reacting proteins:

As a consequnece of high sequence identity to other members of the Bet v 1 family IgE to Pru av 1 cross-reacts with pathogenesis related proteins from parsley, potato, soya bean, Mal d 1 from apple, and Bet v 1 from birch pollen (Scheurer et al. 1997, 1999).

Allergen properties & biological function:Pru av 1 is a member of pathogenesis-related protein group 10. These proteins are expressed upon pathogen attack, stress and abiotic stimuli. Although, Pru av 1 precise function is not known, same evidence is given that Pru av1 is involved in steroid binding (Neudecker et al 2000; Neudecker et al 2001).

The thaumatin-like proteins (TLPs) contain 8 disulfide bridgesand so it might be expected to be thermostable. The TPLs are generally resistant to proteases and pH-induced denaturation (Breiteneder, H. 2004) [1001]

Nature of main cross-reacting proteins:Not known

Allergen properties & biological function:Pru av 2 has significant similarities to other thaumatin-like proteins belonging to pathogenesis-related protein group 5 and are thought to be produced in response to pathogen infection or to osmotic stress. (Inschlag et al. 1998)

Nature of main cross-reacting proteins:Sequence identity of Pru av 3 with that of almond (89%), peach Pru p 3 (87.9%) and apricot Pru ar 3 (85.7%) indicates that IgE cross-reactivity between these proteins is likely.

Allergen properties & biological function:

Plant nonspecific lipid-transfer proteins are thought to be involved in transport of fatty acids both intracellular and extracellularly and of cutin monomers to the cuticular layer of leaves and fruits. There is an expandable cavity between the four alpha-helices which can bind one or two lipids. nsLTPs have also been reported to act as plant defense proteins against bacterial and fungal infections and form the PR14 family of pathogenesis related proteins. It is possible that a lipid-like post-translational modification is involved (Lindorff-Larsen et al. 2001 [903]).

Allergen purification:Cherry LTP purified from fruit has not been reported, but prepared using a heterologous expression system, E. coli, as a His tag fusion protein and was purified on nickel-nitrilotriacetate solid-phase (Scheurer et al. 2001)

There are only few studies on the stability of profilins most of them on celery profilin. Compared to other allergens, profilin is a moderately stable protein, more resistant than Bet v 1 homologues but less stable than lipid transfer proteins or cross-reactive carbohydrate deteminants of glycoprotein allergens.